Aromatic hydroxythiol synthesis using diazonium salts

ABSTRACT

A method for the preparation of aromatic hydroxythiols including oxidizing an aromatic aminothiol to form an aminodisulfide compound; forming a bis-diazonium salt of the aminodisulfide compound; and reacting the bis-diazonium salt with water to form an aromatic hydroxyldisulfide compound, which is then reduced to the hydroxythiol. New bis-diazonium aromatic disulfide compounds are also disclosed.

FIELD OF THE INVENTION

The present invention relates to the preparation of aromatichydroxythiol compounds, and, more specifically, to the preparation ofisomerically pure hydroxythiophenols. In particular, the presentinvention relates to a commercially feasible hydroxythiophenol synthesisin which significant quantities of the isomerically pure reactionproduct are obtained.

DESCRIPTION OF THE PRIOR ART

Diazonium salt reactions are generally employed to substitute anaromatic ring with a hydroxyl group. The diazonium salt reaction ofaromatic thiols, however, produces a poor yield of diazonium salt.Furthermore, aromatic thiols are nucleophiles that tend to reactviolently with diazonium reagents.

Isomerically pure hydroxythiophenols are important reagents and startingmaterials for a variety of pharmaceutical, agrochemical and chemicalprocesses. 3-Hydroxythiophenol, in particular, has been used as a keystarting material for the synthesis of a new drug for the prevention ofbreast cancer. The commercial demands for these compounds have created aneed for their practical large scale production.

An isomerically pure hydroxythiophenol could be prepared by reacting anisomerically pure aminothiophenol with NaNO₂ and H₂ SO₄ to form thecorresponding diazonium salt, which could then be converted to ahydroxythiophenol by reaction with water. However, consistent with otheraromatic thiol compounds, low yields are obtained. There remains a needfor a commercially practical method of producing isomerically purehydroxythiophenols in high yield.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

This need is met by the present invention. It has now been discoveredthat oxidation of aromatic thiols to create a disulfide linkage betweentwo thiol groups eliminates the reactivity of the thiol sulfur towarddiazonium reagents. The use of the disulfide structure as an internalself-protecting group eliminates the need for additional reagents forcarrying out protection of the thiophenol group. This is particularlyadvantageous for the production of isomerically pure hydroxythiophenols.

Furthermore, many of the process steps can be performed in one pot,without the intervening extraction and washing steps. Species are notformed by de-protection of the thiophenol that would require removal inan additional washing step.

The present invention thus provides an improved method the preparationof aromatic hydroxythiol compounds in which, as shown in Step I, anaromatic aminothiol compound is oxidized to form an aromaticaminodisulfide:

Step I: ##STR1## Ar is selected from aryl, aralkyl or heterocyclic ringsor a fused ring structure of from two to ten of such rings. Thebis-diazonium salt of the aromatic aminodisulfide is then formed, asshown in Step II, by treating the aromatic aminodisulfide with NaNO₂ andH₂ SO₄ :

Step II: ##STR2##

The bis-diazonium salt is then reacted with water, as shown in Step III,to form an aromatic hydroxyldisulfide compound:

Step III: ##STR3##

The disulfide bond is then reduced, as shown in Step IV, to obtain thearomatic hydroxythiol compound:

Step IV: ##STR4##

Because the reaction itself does not generate isomers, the method of thepresent invention is useful for the synthesis of isomerically purearomatic hydroxythiol compounds, and particularly useful for thesynthesis of isomerically pure hydroxythiophenol compounds.Hydroxythiophenol synthesis is depicted in Steps I-IV when Ar is anunsubstituted or substituted phenyl group.

For purposes of the present invention, an "isomerically pure" reactionproduct contains the same level of isomeric impurities as its startingmaterial. Therefore, with the method of the present invention, theisomeric purity of the reaction product will depend upon the isomericpurity of its starting material, and it is possible to obtain anisomeric purity of 95 wt % and greater. Thus, to obtain an isomericallypure end product, an isomerically pure starting material must beemployed.

Another aspect of the present invention provides bis-diazonium saltcompounds having the structure depicted in Formula I:

    X.sup.-+ N.sub.2 --Ar--S--S--Ar--N.sub.2.sup.+ X.sup.-     (I)

Both Ar groups are the same and are selected from divalent substitutedor unsubstituted aromatic radicals, divalent substituted orunsubstituted araliphatic radicals, divalent substituted orunsubstituted heterocyclic radicals and fused ring structures formedtherefrom containing from two to ten rings.

The method of the present invention utilizes aromatic aminothiolcompounds as starting materials. The compounds are commerciallyavailable. Alternately, they may be prepared using essentiallyconventional techniques. Aromatic aminothiol starting materials suitablefor use with the present invention have the structure of Formula II:

    H.sub.2 N--Ar--SH                                          (II)

Ar is as described above for Formula I. More preferably, Ar is asubstituted or unsubstituted C₆ -C₁₅ aryl radical, a substituted orunsubstituted C₇ -C₁₃ aralkyl radical, a substituted or unsubstituted3-6 member heterocyclic radical, or a two or three ring fused ringstructure of any of the foregoing. Essentially any substitution groupsthat are inert toward diazonium salt-forming reagents or are capable ofbeing protected from reaction with diazonium salt-forming reagents maybe employed. Suitable substitution groups, substitution groups requiringprotecting groups, protecting groups and methods of protection arewell-known. Examples of substitution groups include C₁ -C₆ aliphaticssuch as alkyls, alkoxys and alkenyls, C₆ -C₁₅ aryls, C₃ -C₈ cyclicaliphatics, amidos and secondary and tertiary aminos.

Ar as a 3-6 ring member heterocyclic radical may include knownheterocyclic atoms such as N, O and S. Suitable heterocycles include,for example, pyran, thiophene, pyrrole, furan, pyridine, or derivativesthereof. Ar as a C₆ -C₁₅ aryl may be, for example, phenyl, o-tolyl,m-tolyl, p-tolyl, o-xylyl, m-xylyl, p-xylyl, alpha-naphthyl orbeta-naphthyl. Ar as a C₇ -C₂₀ aralkyl radical may be, for example,benzyl, 4-methylbenzyl, o-methylbenzyl, p-methylbenzyl, diphenylmethyl,2-phenylethyl, 2-phenylpropyl or 3-phenylpropyl, and preferably a C₇ -C₉aralkyl, especially benzyl. Any of these groups may be substituted, forexample, with substituted or unsubstituted, straight-chained or branchedC₁ -C₂₀ alkyl, aryl, aralkyl, amido, alkoxyl and secondary and tertiaryamino groups.

In a preferred embodiment, Ar is C₆ -C₁₄ aryl, especially phenyl ornaphthyl. When the aryl or aralkyl group of Ar is a phenyl oralkylphenyl group the compound of Formula II is a starting material forhydroxythiophenols having the structure of Formula III: ##STR5## Y isselected from straight-chained or branched, unsubstituted or substitutedC₁ -C₂₀ alkyl, aryl, aralkyl, amido, alkoxyl and secondary and tertiaryamino groups; and n is between 0 and 4, inclusive.

The aromatic aminothiol starting materials can be obtained commercially,or, as shown below, by reducing corresponding aromatic nitrosulfonylchlorides:

Scheme I: ##STR6## Essentially any well-known reagent capable ofreducing an aromatic nitrosulfonyl chloride to an aromatic thiophenolcan be used. Suitable reagents, solvents and process conditions may bedetermined by reference to March, J., Advanced Organic Chemistry (2ndEd., McGraw-Hill, 1977), (the disclosure of which is incorporated hereinby reference) and through routine optimization of reaction parameters.Examples of suitable reducing agents include hydroiodic acid,metal/concentrated mineral acid combinations such as Zn, Sn or Fe andconcentrated hydrochloric or sulfuric acid, or hydrides such as NaBH₄ orLiAlH₄.

The aromatic aminothiol starting materials can also be made, as shown inScheme II, by reducing aromatic aminosulfonic acids and derivativesthereof after the amine function has been suitably protected:

Scheme II: ##STR7## Suitable reagents, solvents, protecting groups,protection reactions and process conditions may be determined byreference to the above-cited Advanced Organic Chemistry, and throughroutine optimization of reaction parameters. PCl₅ can be used instead ofSO₂ Cl. The reducing agents used in Scheme I can also be used in SchemeII.

Accordingly, isomerically pure end products may be obtained by startingwith isomerically pure aromatic nitrosulfonyl chlorides, which are alsocommercially available or may be prepared by known methods. Isomericallypure aromatic nitrosulfonyl chlorides, when not available commercially,are prepared using well-known nitration and sulfonation reactions.Suitable reagents, solvents and process conditions may by determined byreference to the above-cited Advanced Organic Chemistry and throughroutine optimization of reaction parameters. The aromatic nitrosulfonylchlorides that form have distinct boiling points and are separated on acommercial scale by distillation.

The aromatic aminothiol compound is then allowed to undergo oxidation inthe Step I to form a disulfide dimer. Essentially any oxidizer capableof forming a sulfur bridge between two thiol groups may be used. Thisreaction step is essentially conventional, and suitable reagents,solvents and process conditions may be determined by reference toYiannios et al., J. Org. Chem., 28, 3246(1963), the disclosure of whichis incorporated herein by reference.

For Example, the oxidation may be performed by heating the aromaticaminothiol with an oxidant such as DMSO or 30% aqueous hydrogen peroxideat a temperature between about 50 and about 150° C., and preferablybetween about 80-90° C., to form disulfide linkages between the thiolgroups, thereby converting the aminothiol compound to an amino disulfidecompound having the structure of Formula IV:

    H.sub.2 N--Ar--S--S--Ar--NH.sub.2                          (IV)

The Ar groups are identical, and are as described above for Formula I.One of ordinary skill in the art will understand that with oxidants suchas hydrogen peroxide that tend to decompose at elevated temperatures,lower temperatures within the 50 to 150° C. range should be employed.

When Ar is a phenyl or alkylphenyl group, the compound is anintermediate in the preparation of hydroxythiophenols having thestructure of Formula V: ##STR8## Y and n are as described above withrespect to Formula III and X is an amino group.

The reaction mixture is washed with cold water and then extracted intoan organic solvent. Essentially any organic solvent in which an aromaticdisulfide is soluble may be employed. Examples include ethers such asMTBE, diethyl ether or isopropyl ether, ethyl acetate or halogenatedsolvents such as dichloromethane or chloroform. The organic phase isthen washed with water and purified by vacuum distillation. These stepsare also essentially conventional, and suitable reagents, solvents andprocess conditions may be determined by reference to the above-citedpublication by Yiannios et al. in J. Org. Chem.

The amino disulfide compound is then allowed to undergo the diazoniumsalt-forming reaction of Step II. This reaction step is also essentiallyconventional, and suitable reagents, solvents and process conditions maybe determined by reference to Cohen et al., J. Org. Chem., 42, 2053(1977), the disclosure of which is incorporated herein by reference. Forexample, the known reaction with NaNO₂ and H₂ SO₄ disclosed in thispublication may be employed.

In this reaction, the aromatic aminodisulfide is dissolved in an aqueoussulfuric acid solution, which is then cooled to a temperature betweenabout 5 and about 40° C. Sodium nitrite is slowly added whilemaintaining the temperature within the foregoing range. One of ordinaryskill in the art will understand that higher reaction temperatures canbe employed with slower rates of addition. After the addition iscompleted, urea is added to consume any excess sodium nitrite,optionally followed by the addition of water. A solution is obtained ofa bis-diazonium salt having the structure of Formula VI:

    X.sup.-+ N.sub.2 --Ar--S--S--Ar--N.sub.2.sup.+ X.sup.-     (VI)

X is a counter-ion and Ar is as described above for Formula I. When Aris a phenyl or alkylphenyl group, the compound is an intermediate in thepreparation of hydroxythiophenols having the structure of Formula VII:##STR9## Y and n are as described above for Formula III, and X is acounter-ion. Examples of typical counter-ions that form include sulfateand hydrosulfate.

The bis-diazonium salt solution is kept cold prior to the replacement ofthe diazonium salt groups with hydroxy groups. The cold solution is thenadded in small portions to an aqueous sulfuric acid solution heated tobetween about 80 and about 150° C., and preferably to about 110° C., atwhich the reaction mixture is maintained for between about 30 minutesand about two hours. A conventional catalyst at room temperature mayalternatively be employed. This reaction step is also essentiallyconventional, and suitable reagents, solvents and process conditions maybe determined by reference to the above-cited publication by Cohen etal. in J. Org. Chem.

The reaction mixture is then cooled to yield an aromatichydroxyldisulfide having the structure of Formula VIII:

    HO--Ar--S--S--Ar--OH                                       (VIII)

Ar is as described above for Formula I. When Ar is a phenyl oralkylphenyl group, the compound is an intermediate in the preparation ofhydroxythiophenols having the structure of Formula V in which each X isa hydroxyl group and Y and n are as described above for Formula III. Thereaction mixture is then extracted as in Step I with an organic solventsuch as an ether, acetate or halogenated hydrocarbon. The organic layeris then concentrated by the well-known technique of evaporation,optionally with reduced pressure, to afford the crude disulfide.

The disulfide linkage is then reduced to liberate the isomerically purearomatic hydroxythiol. Essentially any agent capable of reducing adisulfide linkage may be used. For example, the disulfide linkage may bereduced by treatment with a reducing agent such as a mixture of sodiummetabisulfite and KOH, or a mixture of a metal (such as Zn, Fe or Sn)and H⁺. Reducing agents such as sodium metabisulfite or metal hydridessuch as sodium borohydride or lithium aluminum hydride may also beemployed. Suitable reagents, solvents and process conditions my bedetermined by reference to the above-cited Advanced Organic Chemistryand through routine optimization of reaction parameters.

The precipitated aromatic hydroxythiols are then isolated from thereaction mixture by extraction as in Step I, with an organic solventsuch as an ether, acetate or halogenated hydrocarbon. The resultingaromatic hydroxythiol has the structure of Formula IX:

    HO--Ar--SH                                                 (IX)

Ar is as described above for Formula I. When Ar is a phenyl oralkylphenyl group, the compound is a hydroxythiophenols having thestructure of Formula V in which each X is a hydroxyl group and Y and nare as described above for Formula III.

EXAMPLES

Unless disclosed to be otherwise, reactions are performed at roomtemperature or at ambient pressure.

Example 1 Preparation of 3-Hydroxythiophenol

3-Aminothiophenol (5 g, 40 mmol) was oxidized to 3-aminophenyl disulfidewith one equivalent dimethyl sulfoxide (DMSO) (20 g, 26 mmol) at 80-90°C. in near quantitative yield as shown by GC. Without isolation, thereaction mixture was poured into a dilute sulfuric acid solution (7.2 mLconcentrated sulfuric acid in 50 mL water) to obtain a milk-like whitesuspension which was doubly diazotized using a solution of NaNO₂ (2.5 g)in water (8 mL) at room temperature. The diazonium salt solution (orangecolor) was then thermally decomposed by carefully dripping into arefluxing solution of sulfuric acid (20 mL) and water (10 mL). A darkbrown mixture was obtained when the addition was completed. The reactionwas monitored by GC by extracting an aliquot into isopropyl ether, whichshowed a near clean formation of the desired disulfide. The reactionmixture was then cooled in an ice-water bath followed by rapid additionof Zn dust. The reaction was gradually warmed to room temperature andheated at reflux. The dark brown color faded away and the reactionmixture became off-white. The reaction was monitored by GC by extractingan aliquot into isopropyl ether. The product 3-hydroxythiophenol wasisolated by isopropyl ether extraction in 73% yield from3-aminothiophenol. Both GC and ¹ H NMR showed good purity.

Example 2 Preparation of 2-Hydroxythiophenol

2-Hydroxythiophenol is prepared according to the method of Example 1,using as the starting material 2-aminophenol.

Example 3 Preparation of 2-Thio-4-Hydroxytoluene

2-Thio-4-hydroxytoluene is prepared according to the method of Example1, using as the starting material 2-thio-4-aminotoluene.

Example 4 Preparation of 2-Thio-5-Hydroxy-p-Xylene

2-Thio-5-hydroxy-p-xylene is prepared according to the method of Example1, using as the starting material 2-thio-5-amino-p-xylene.

Example 5 Preparation of 1-Thio-4-Hydroxy-Naphthalene

1-Thio-4-hydroxy-naphthalene is prepared according to the method ofExample 1, using as the starting material 1-thio-4-amino-naphthalene.

Example 6 Preparation of 2-Thio-3-Hydroxy-Thiophene

2-Thio-3-hydroxy-thiophene is prepared according to the method ofExample 1, using as the starting material 2-thio-3-amino-thiophene.

Example 7 Preparation of 2-Thio-4-Hydroxy-Furan

2-Thio-4-hydroxy-furan is prepared according to the method of Example 1,using as the starting material 2-thio-4-amino-furan.

Example 8 Preparation of 2-Thio-3-Hydroxy-Pyrrole

2-Thio-3-hydroxy-pyrrole is prepared according to the method of Example1, using as the starting material 2-thio-3-amino-pyrrole.

The present invention thus provides a practical, commercially viablemethod for the preparation of hydroxythiophenols from readily availablestarting materials.

What is claimed is:
 1. A method for the preparation of aromatic hydroxythiols comprising the steps of oxidizing a diazonium salt-forming aromatic aminothiol to form an aminodisulfide compound; forming a bis-diazonium salt of said aminodisulfide compound; and reacting said bis-diazonium salt with water to form an aromatic hydroxyldisulfide compound.
 2. The method of claim 1, further comprising the step of reducing the disulfide bond of said disulfide to form an aromatic hydroxythiol.
 3. The method of claim 1, wherein said aromatic aminothiol has the structure:

    H.sub.2 N--Ar--SH

wherein Ar is selected from the group consisting of substituted or unsubstituted aromatic radicals, substituted or unsubstituted araliphatic radicals, substituted or unsubstituted heterocyclic radicals and fused ring structures formed therefrom containing from two to ten rings.
 4. The method of claim 3, wherein Ar is selected from the group consisting of substituted or unsubstituted C₆ -C₁₅ aryl radicals, substituted or unsubstituted C₇ -C₁₃ aralkyl radicals, substituted or unsubstituted 3-6 member heterocyclic radicals, or a two or three ring fused ring structure thereof.
 5. The method of claim 4, wherein Ar is a phenyl group.
 6. The method of claim 5, wherein Ar is a phenyl group substituted with one or two moieties selected from the group consisting of straight-chained and branched, substituted and unsubstituted C₁ -C₂₀ alkyl, aryl, aralkyl, amido, alkoxyl, secondary amino and tertiary amino groups.
 7. The method of claim 6, wherein said phenyl group is substituted with one or two aralkyl, aryl, alkyl or tertiary amino groups.
 8. The method of claim 5, wherein Ar is an unsubstituted phenyl group.
 9. The method of claim 8, wherein said aromatic aminothiol is an ortho-aminothiophenol.
 10. The method of claim 8, wherein said aromatic aminothiol is a meta-aminothiophenol.
 11. The method of claim 8, wherein said aromatic aminothiol is a para-aminothiophenol.
 12. The method of claim 1, wherein said aromatic aminothiol has the structure: ##STR10## wherein Y is selected from the group consisting of straight-chained and branched, substituted and unsubstituted C₁ -C₂₀ alkyl, aryl, aralkyl, amido, alkoxyl, secondary amino and tertiary amino groups; and n is between 0 and 4, inclusive.
 13. The method of claim 12, wherein n is
 0. 14. The method of claim 13, wherein the NH₂ group is meta to the SH group. 